Transient interactions between the fuzzy coat and the cross-b core of brain-derived Ab42 filaments

This study investigates the structural properties of amyloid fibrils, prevalent in various human disorders, including Alzheimer's disease. Using the metadynamic electron microscopy metainference (MEMMI) approach, conformational ensembles were generated for two types of amyloid filaments associated with familial and sporadic forms of AD. The results revealed that familial AD filaments exhibit lower solubility compared to sporadic AD filaments, and the fuzzy coat, a disordered region, contributes to increasing the solubility of both filament types. Additionally, analysis of density maps from cryo-EM and MEMMI structural ensembles showed a slowing down of water and sodium ion diffusion near the filament surface, providing insights into the hydration dynamics of amyloid fibrils. This study demonstrates the utility of the metainference approach in analyzing cryo-EM maps for characterizing the properties of amyloid fibrils.